Thiamin-procaine anesthetic



Patented Oct. 11, 1949 UNlTED STATES FFICE No Drawing. Application July 10, 1947, Serial No. 760,127

2 Claims.

My invention relates to thiamin-procaine anesthetic and refers particularly to anesthesia procaine and procaine hydrochloride.

The value of procaine hydrochloride as a local anesthetic is recognized and it is used largely in regional and spinal anesthesia, dental operations and in many operations where local anesthesia is desired.

While the adoption of procaine hydrochloride as a spinal injection is general, its lethal properties are recognized and its successful application requires extreme care with a proper consideration of the physical and nervous condition of the patient.

The usual causes of immediate death from spinal injections of procaine hydrochloride are attributed to respiratory and cardiac failure, while delayed deaths are attributed to shock.

It is evident, therefore, that if the lethal dose of procaine hydrochloride could be increased, larger quantities could be injected with a consequent increase in the time of its efiectiveness.

It is also evident that as immediate deaths are due to respiratory and cardiac failures, any means adapted for the strengthening of these systems during the operating period will allow of increased doses of the anesthesia with increased periods of its effectiveness.

My efforts, therefore, were directed to deterwould affect either the anesthesia itself or the respiratory or cardiac system whereby the lethal dose of the anesthesia would be increased, or its anesthetic efiects prolonged or both.

My experiments showed that some compounds various compounds which reduced the lethal dose of procaine hydrochloride.

It was found that pneumonia, marked postoperative infection, and certain hypotensive states produced by hemorrhage, amyl nitrite, and histamine all reduced the lethal dose of procaine suf- 1 ficient to cause paralysis of the respiratory center. The probability of a relationship between anoxia and this reduction of the lethal dose of procaine was pointed out.

Sodium amytal and large doses of morphine t: results. mining some compound or compounds, which 'inations.

cause a marked reduction of the minimum lethal dose.

In the presence of infection, or alkalosis, the need for vitamin B1 is particularly increased. It is reasonable to assume the reserve supply of this vitamin for the nerve cells is lowered in these states, as well as in chronic illnesses and cachexia. The vitamin B1 content of cerebrospinal fluid has been found below normal in certain chronic neurological conditions. Contact of the anesthetic drug with nerve structures under such circumstances may produce changes which are irreversible, leading to diplopia, atrophy or paralysis of isolated muscles, and psychic reflex sequelae.

I, thereupon, made numerous tests with thiamin chloride (vitamin B1) in connection with procaine hydrochloride, from which the following are cited.

A series of 273 adult cats and '5 rhesus monkeys were given intra-cisternal injections under light ether anesthesia. The introduction of a needle into the cisterna magna is accompanied by some danger of subarachnoid hemorrhage, and puncture of the vital areas. The former may so dilute any subsequent injection of a drug as to make the observations valueless. The latter usually results in prompt exodus of the animal. Where the puncture injures the lower closed part of the medulla, ataxia or paralysis, usually of the hind limbs, Only those animals were considered in which the cisternal tap afforded a free flow of clear or only very slightly blood-tinged spinal fluid, and where one could be sure that no injury to nerve tissue had occurred.

Of the 273 cats, 32 had to be discarded on account of these technical difficulties. With increased experience and improved technique, only one cat had to be discarded in the last 100 used. 275 injections were given cisternally to 241 cats, and the observations on these animals form the basis for the following.

The immediate eiiects of various concentrations and amounts of procaine hydrochloride, thiamin chloride (vitamin B1), and mixtures of these two drugs upon the vital centers were observed. A comparative study of all available spinal anesthetic drugs was likewise made. An attempt was also made to determine the extent and duration of any anesthesia resulting from these drugs after a lapse of 10 to 15 minutes which was the recovery time from the efiects of the ether alone. Some of these animals were observed over a period of days, and were sacrificed at intervals in order to obtain the nervous systems for pathological exam- 45 autopsies were performed on the procaine, vitamin B1, and procaine-vitamin B1 groups. In no case, however, were any signs of gross pathology noted in the brains or spinal cords, or their coverings, with the exception that in those animals dying soon after convulsions produced by large doses of vitamin B1, the blood vessels overlying the brain appeared distended.

Besides the various factors itemized in the summaries of the experiments, unmeasurable factors such as the state of general and vitamin nutrition undoubtedly influenced the tolerance to the drugs injected.

In the first group of 51 cats, 59 injections of I procaine hydrochloride were given in doses of from 7.5 mg. up to 45 mg., and in concentrations of from 0.75% to 11.66%. The cats. usually survived the injections of amounts up to mg. With 20 mg. or more, respiratory paralysisresulted in death in from 2% to 20 minutes; in each case the heart continued to beat for some time after respiration had ceased. A lethal dose of 77% was found for 20 mg. procaine hydrochloride (13 cats), while alethal dose of 83% was found for 30 mg. (18 cats). It is evident that 15 mg. is about the maximum safe dose for cats, intracisternally.

Anesthesia lasting over 15 minutes was not observed except in those occasional cats which survived injections of mg. or more. it is the final concentration of the procaine in contact with the respiratory center which determines Whether the animal will live or not, and this depends upon the amount of cerebro-spinal fluid removed, the amount left behind, and the volume of the solution injected.

In addition, however, there is the factor of individual susceptibility Or resistance of the nerve centers to such drugs as procaine hydrochloride. It is not unlikely that the vitality of the individual neurones making up the centers are conditioned by the state of vitamin nutrition, particularly of vitamin B1.

Another group of 15 cats were given 16 injections of thiamin chloride (yitamin B1) intracisternally, in doses of from 1 to 90 mgs. Definite stimulation of respiration was noted with doses over 1 0 mg, marked stimulation with doses over 20 mg.

In the present series of experiments, convulsions were noted with doses of from 15 to 90 mg. vitamin B1 cisternally. Some animals survived repeated generalized convulsions for periods of over one hour; others died after convulsions lasting from 40 minutes to over 3 hours. With the largest dose of 90 mg. death resulted in five minutes before any convulsions could develop.

In the third group, thiamin chloride (vitamin B1) was combined with procaine hydrochloride in varying proportions. 75 such cisternal injections were given to '72 cats.

A small dose of 5 mg. procaine hydrochloride was found to protect against a lethal dose of 90 mg. vitamin B1, while 5 mg, of vitamin B1 protected against a lethal dose of and mg. pro- V caine hydrochloride.

The procaine hydrochloride was increased to as much as 100 mg, and some injections contained as much as 110 mg. vitamin B1.

It could be readily seen from a compilation of the results that by combining vitamin B1 with procaine hydrochloride, the toxicity of the latter drug is diminished. In one case 5 times the lethal dose (77%) could be given and the animal survived. It is conservative to say that the maximum Undoubtedly safe dose of procaine hydrochloride can safely be doubled when combined with vitamin B1.

Where more than 5 mg. procaine hydrochloride were used with vitamin B1, no convulsions developed, although in some animals there was definite evidence of respiratory stimulation. A combination in which the amount of vitamin B1 was half the dose of procaine hydrochloride appeared to give safe protection without undue respiratory stimulation, or impairment of anesthesia time.

A comparative study of the toxicity of other spinal anesthetics was tested in a similar manner by intracisternal injections in cats. The drugs used and their relative toxicities as tested for respiratory paralysis, were as follows:

'Procaine hydrochloride=l Pontocaine (Winthrop), toxicity 40 Nupercaine (Ciba) 40 Cocaine hydrochloride (Merck) 4 Stovaine (Poulene Freres) 4 Metycaine (Lilly) 3 Tropococaine hydrochloride (Merck) 2 Tutocaine (Winthrop) 1.5 Apothesine (Parke, Davis) 1.5 Novocaine (Winthrop) 1 Neocaine (Anglo-French) 1 Aminccaine (Seydel) 0.5

It is interesting to note that aminocaine alone proved to be the safest drug, but that when combined with thiamin chloride, its toxicity increased. The toxicities of pontocaine and metycaine likewise increased when vitamin B1 was combined with them. Procaine hydrochloride combined with thiamin chloride proved to be the safest combination, allowing the largest amount of anesthetic drug to be given.

With the results of my experiments in mind, the suggestion is made that the combination of procaine hydrochloride with vitamin B1 in a proportion of 2 to 1 will produce the safest spinal anesthesia yet obtainable.

The use of such a combination should permit larger doses of the anesthetic drug to be given. Spinal anesthesia lasting many times the duration now possible may be obtained from larger doses. Whereas the maximum safe dose of procaine hydrochloride alone is now 200 mg. in the lumbar region, as much as 1000 mg. might be given in the same region if a sufiicient amount of vitamin B1 is given simultaneously.

By adding this safety factor of vitamin B1, the respiratory center should be protected against paralysis. Total'spinal anesthesia should receive a new impetus. New clinical uses for this type of prolonged anesthesia will undoubtedly be found, particularly in prolonged operations for cancer. Continuous or fractional spinal anesthesia with procaine-vitamin B1 should prove superior to any other type of anesthesia required for operations lasting several hours. In the terminal stages of cancer, when all narcotic fail, a continuous spinal-drip of procaine-vitamin B1 may be the only method of stopping the intractable pains short of euthanasia.

An attempt to find another drug which would have the same power as vitamin B1 to stimulate the respiratory center when given cisternally was unsuccessful. Among the drugs tried were thiazole, pyrimidine, nicotinic acid, nicotinamide, hydrochloric acid (1:1000), ephedrine sulfate, adrenaline, caffeine sodium benzoate, strychnine, camphor in oil, atropine, pituitary extracts, er-

gotamine tartrate, ammonium chloride, and

B1 has the unique property of stimulating respiration has been shown by these experiments. Failure of dilute hydrochloric acid and of histamine rule out the possibility that the stimulating action is due to irritation.

Since thiamin chloride has been shown to have such a marked stimulating effect upon the respiratory center when given intraspinally, it is suggested that this drug may prove a life saving measure in cases of poliomyelitis, gas poisoning, drowning, electric shock, snake and drug poisoning, or or in any condition where the respiratory center is depressed. It is suggested that vitamin B1 might be routinely used whenever morphine is given. It might likewise be combined to advantage with cocaine or its derivatives for use in local anesthesia, with the exception of those few drugs whose toxicity is increased by the combination with the vitamin.

REFERENCES CITED The following references are of record in the file of this patent:

Merck's Index, 1940, 5th ed., pages 577, 578. Copy in Division 43. 

